The predominant application of anticonvulsant drugs is the control and prevention of seizures associated with epilepsy or related central nervous system disorders. Epilepsy refers to many types of recurrent seizures produced by paroxysmal excessive neuronal discharges in the brain; the two main generalized seizures are petit mal, which is associated with myoclonic jerks, akinetic seizures, transient loss of consciousness, but without convulsion; and grand mal which manifests in a continuous series of seizures and convulsions with loss of consciousness.
The mainstay of treatment for such disorders has been long-term and consistent administration of anticonvulsant drugs. Most drugs in use presumably exert their action on neurons, glial cells or both of the central nervous system. The majority of these compounds are characterized by the presence of at least one amide unit and one or more benzene rings that are present as a phenyl group or as part of a cyclic system.
Much attention has been focused upon the development of anticonvulsant drugs. As a result many such drugs have been prepared. For example, the hydantoins, such as phenytoin, are useful in the control of generalized seizures and all forms of partial seizures. The oxazolidinediones, such as trimethadione and paramethadione, are used in the treatment of nonconvulsive seizures. Phenacemide, a phenylacetylurea, is one of the anticonvulsants employed today. However recently, much attention has been focused on diazepines and piperazines. For example, U.S. Pat. Nos. 4,002,764 and 4,178,378 to Allgeier, et al. disclose esterified diazepine derivatives useful in the treatment of epilepsy and other nervous disorders. U.S. Pat. No. 3,887,543 to Nakanishi, et al. describes a thieno 2,3-e! 1,4! diazepine compound also having anticonvulsant activity and other depressant activity. U.S. Pat. No. 4,209,516 to Heckendorn, et al. relates to triazole derivatives which exhibit anticonvulsant activity and are useful in the treatment of epilepsy and conditions of tension and agitation. U.S. Pat. No. 4,372,974 to Fish, et al. discloses a pharmaceutical formulation containing an aliphatic amino acid compound in which the carboxylic acid and primary amine are separated by three or four units. Administration of these compounds in an acid pH range is useful in the treatment of convulsion disorders and also possess anxiolytic and sedative properties.
U.S. Pat. No. 5,378,729 to Kohn, et al. discloses compounds and pharmaceutical compositions having central nervous system (CNS) activity which are useful in the treatment of epilepsy and other CNS disorders having the formula: ##STR2## wherein
R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or substituted with at least one election withdrawing group or election donating group;
R.sub.1 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloaklyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group;
R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y, wherein R.sub.2 and R.sub.3 may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group:
Z is O, S, S (O).sub.a, NR.sub.4, PR.sub.4 or chemical bond;
Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic or heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided that when Y is halo, Z is a chemical bond; or
ZY taken together is NR.sub.4 NR.sub.5 R.sub.7, NR.sub.4 OR.sub.5, ONR.sub.4 R.sub.7, OPR.sub.4 R.sub.5, PR.sub.4 OR.sub.5, SNR.sub.4 R.sub.7, NR.sub.4 SR.sub.7, SPR.sub.4 R.sub.7, PR.sub.4 SR.sub.7, NR.sub.4 PR.sub.5 R.sub.6, ##STR3##
R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R.sub.4, R.sub.5, and R.sub.6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group;
R.sub.7 is R.sub.6, COOR.sub.8 or COR.sub.8 ;
R.sub.8 is hydrogen, lower alkyl or aryl lower alkyl and the aryl or alkyl group may be unsubtituted or substituted with an electron withdrawing group or an electron donating group;
n is 1-4 and
a is 1-3.
Unfortunately, despite the many available pharmacotherapeutic agents for the treatment of epilepsy, a significant percentage of the population with epilepsy still suffers from this malady. Moreover, none of the drugs presently available are capable of achieving total seizure control and most have disturbing side effects. Clearly, current therapy has failed to fully control these debilitating diseases.
These shortcomings of these drugs on the market has prompted the present inventor to find new drugs having anticonvulsant properties. The present invention provides novel compounds exhibiting CNS activity, particularly anticonvulsant activity, which are useful for treating epilepsy and other CNS disorders.